PL212238B1 - Novel medicaments for the treatment of chronic obstructive pulmonary diseases - Google Patents

Abstract

The use of 2-(N-(1,1-dimethyl-omega -phenyl-alkyl)-amino)-1-(6-hydroxy-4H-benz-(1,4)-oxazin-3-on-8-yl)-ethanol derivatives (I) for treating chronic obstructive pulmonary disease (COPD) is new. The use of benzoxazinonyl-ethanolamine derivatives of formula (I) (including individual optical isomers, enantiomer mixtures and racemates) or their acid addition salts is claimed in the production of medicaments for treating chronic obstructive pulmonary disease (COPD). [Image] n : 1 or 2; R 1>, R 2>H, alkyl, halo, OH or alkoxy; R 3>H, alkyl, OH, halo, alkoxy, carboxyalkoxy or alkoxycarbonylalkoxy; alkyl moieties have 1-4C. Independent claims are included for: (a) inhalable pharmaceutical formulations containing (I); and (b) new benzoxazinonyl-ethanolamine derivatives of formula (I') (including optical isomers, salts etc.). [Image] n : 1; R 1>', R 2>' : H or alkyl; R 3>' : alkyl, OH, alkoxy, carboxyalkoxy or alkoxycarbonylalkoxy; and provided that: (1) alkyl moieties have 1-4C; and (2) if R 1> and R 2> are both ortho-methyl, then R 3> is not OH. ACTIVITY : Antiinflammatory. MECHANISM OF ACTION : beta -Mimetic.

Description

The subject of the invention are new betamimetic compounds of the general formula 1:

2 3 wherein R ^1, R ² and R ³ are as defined in the claims and the description as well as the use of these compounds for the manufacture of a medicament for the treatment of COPD (chronic obstructive pulmonary disease - ang. Chronic obstructive pulmonary disease) as well as a pharmaceutical formulation containing a compound of general formula 1.

Beta-mimetic compounds (β-adrenergic substances) are known in the art. Reference is made here to published US Patent No. 4,460,581, which proposes beta mimetic compounds for the treatment of various diseases.

EP 073 505 A (equivalent to PL No. 139 375) discloses benzoheterocyclic compounds with formulas similar to those of the general formula I and having broncholytic, spasmolytic and antiallergic properties. However, the mentioned publications disclose other compounds which have pharmacological properties which are completely different from those of the invention, and thus they are not the same compounds. Some betamimetic compounds have not yet been disclosed in the prior art.

When treating diseases with medicaments, it is often desirable to deliver drugs with a longer duration of action. In this way, it is generally possible to ensure that the concentration of the active ingredient in the body required for the therapeutic effect is maintained over a longer period of time without the need for too frequent, repeated administration of the medicament. Moreover, the application of the active ingredient at longer intervals contributes significantly to the well-being of the patient.

It is especially desirable to formulate a medicament which is therapeutically effective to be administered by single administration throughout the day (single dose). Administration as follows once a day has the advantage that the patient may become accustomed relatively quickly to taking the drug regularly at certain times of the day.

The object of the invention is therefore to provide beta-amino substances which, on the one hand, have a therapeutic benefit in the treatment of COPD and, moreover, have a longer duration of action and can therefore be used for the production of medicaments with longer activity. The object of the invention is in particular to provide betamimetic substances which, due to their long-lasting activity, can be used in the preparation of a medicament for the treatment of COPD, which agent can be administered once a day. In addition to the above-mentioned objectives, it is an object of the invention to provide such beta-mimetic substances which are not only extremely active, but also have a high selectivity for the β2 adrenoreceptor.

It has surprisingly been found that the above-mentioned problems can be solved with the compounds according to the invention.

According to the invention, these are compounds of the general formula I:

PL 212 238 B1 in which:

n is 1, ₁

R ¹ represents a hydrogen atom, a halogen atom, a C1-C4-alkyl or a -O-C1-C4-alkyl group, ₂

R ² is hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₃

R ³ is C1-C4-alkyl, OH, halogen, -O-C1-C4-alkyl, -O-C1-C4-alkyl-leneCOOH or -O-C1-C4-alkylene-CO-O- C1-C4-alkyl, with the proviso that when R ¹ and R ² each represent a methyl group at the ortho position, R ₃ is ³ may not simultaneously represent OH group.

According to the invention, compounds of the general formula I are preferred, in which:

n is 1, ₁

R ¹ is hydrogen, fluoro, chloro, methyl or methoxy, ₂

R ² is hydrogen, fluoro, chloro, methyl or methoxy, ₃

R ³ is C1-C4-alkyl, OH, fluoro, chlorine, bromine, -O-C1-C4-alkyl, -O-C1-C4-alkylene-COOH, -O-C1-C4-alkylene- CO-O-C1-C4-alkyl, provided that when R ¹ and R ² _{are each 3} times ortho methyl, R ³ cannot simultaneously be an OH group.

Compounds of the general formula I are preferred in which: n is 1,

R is hydrogen or C1-C4-alkyl,

R is hydrogen or C1-C4-alkyl,

R is C1-C4-alkyl, OH, -O-C1-C4-alkyl, -O-C1-C4-alkyl,

2 3 with the proviso that when R ¹ and R ² are each ortho methyl, R ³ cannot simultaneously be an OH group.

Furthermore, compounds of the general formula I are preferred in which:

n is 1, ₁

R ¹ is hydrogen, methyl or ethyl, ₂

R ² is hydrogen, methyl or ethyl, ₃

R ³ is methyl, ethyl, OH, methoxy, ethoxy, -O-CH2-COOH group, -O12 group

-CH2-COO-methyl or -O-CH2-COO-ethyl, with the proviso that when R ¹ and R ² each represent a methyl group, a ₃ in the ortho-position, R ³ may not simultaneously represent OH group.

₃

Equally preferred are compounds of general formula I in which R ³ is methoxy, ethoxy, -O-CH2-COOH, -O-CH2-COO-methyl or -O-CH2-COO-ethyl and R ¹ , R ² , R ^{3 and} n have the same meaning as previously given.

Particularly preferred are compounds of the general formula I according to the invention in which:

n is 1, ₁

R ¹ is halogen, C 1 -C 4 -alkyl or -O-C 1 -C 4 -alkyl, ₂

R ² is halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₃

R ³ is halogen, C 1 -C 4 -alkyl or -O-C 1 -C 4 -alkyl, and compounds of general formula I are more preferred in which:

n is 1, ₁

R ¹ is fluoro, chloro, methyl or methoxy, ₂

R ² is fluoro, chloro, methyl or methoxy, ₃

R ³ is fluoro, chloro, methyl or methoxy.

Preference is given to compounds of the general formula I according to the invention in which:

n is 1, ₁

R ¹ is hydrogen, ₂

R ² is hydrogen, fluoro, chloro or methyl, ₃

R ³ is methyl, ethyl, isopropyl, t-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH2-COOH, -O-CH2-CH2-COOH, -O-CH2-CH2 -CH2- COOH, -O-CH2-COO-methyl, -O-CH2-COO-ethyl, -O-CH2-CH2-COO-methyl, -O-CH2-CH2-COO-ethyl, -O-CH2 -CH2-CH2-COO-methyl, -O-CH2-CH2-CH2-COO-ethyl, and especially preferred are compounds of general formula I in which:

n is 1, ₁

R ¹ is hydrogen, ₂

R ² is hydrogen, fluoro, chloro or methyl, ₃

R ³ is OH, fluoro, chloro, methyl, methoxy, ethoxy or -O-CH2-COOH,

And even more preferred are compounds according to the invention of the general formula I in which:

n is 1,

R ¹ and R ² are hydrogen, ₃

R ³ is methyl, ethyl, isopropyl, t-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH2-COOH, -O-CH2-CH2-COOH, -O-CH2-CH2 -CH2- COOH, -O-CH2-COO-methyl, -O-CH2-COO-ethyl, -O-CH2-CH2-COO-methyl, -O-CH2-CH2-COO-ethyl, -O-CH2 -CH2-CH2-COO-methyl, -O-CH2-CH2-CH2-COO-ethyl, of which the most preferred are compounds of general formula I in which:

n is 1,

R ¹ and R ² are hydrogen, ₃

R ³ is OH, fluoro, chloro, methoxy, ethoxy, -O-CH2-COOH, preferably OH, fluoro, chloro, ethoxy or methoxy.

According to the invention, also preferred are compounds of the general formula I in which:

n is 1, ₁

R ¹ is hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₂

R ² is hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkiIową ₃

R ³ is hydrogen, and particularly preferred of these are compounds of general formula I in which:

n is 1, ₁

R ¹ is hydrogen, fluoro, chloro, methyl or methoxy, ₂

R ² is hydrogen, fluoro, chloro, methyl or methoxy, ₃

R ³ is hydrogen.

A further preferred aspect of the invention relates to a compound of the general formula I in which it has the following structure:

Another preferred aspect of the invention relates to a compound of general formula I, in which it has the following structure:

Yet another preferred aspect of the invention relates to a compound having the following structure:

of general formula I, in which it has

PL 212 238 B1

Yet another preferred aspect of the invention relates to a compound of general formula I wherein it has the following structure:

A further preferred aspect of the invention relates to a compound of the general formula I in which it has the following structure:

Particularly preferred are compounds of general formula I according to the invention which exist in the form of individual optical isomers, mixtures of individual enantiomers or racemates, preferably in the form of enantiomerically pure compounds.

Equally preferred are the compounds of general formula I according to the invention in which the compounds of formula I are present in the form of addition salts with pharmacologically acceptable acids and, if appropriate, in the form of solvates and / or hydrates.

The invention also relates to the use of compounds of general formula I.

The use of the compounds of general formula I as defined in the invention is characterized in that they are used as medicaments.

For the use according to the invention, it is preferred that the compounds of general formula I as defined in the invention are used for the preparation of a medicament for the treatment of chronic obstructive pulmonary disease (COPD).

The invention also relates to a pharmaceutical formulation.

The pharmaceutical preparation according to the invention is characterized in that it contains a compound of general formula I as defined in the invention.

The invention also relates to a pharmaceutical formulation for administration by inhalation.

The pharmaceutical preparation for administration by inhalation is characterized in that it contains a compound of general formula I as defined in the invention.

For a pharmaceutical preparation for administration by inhalation, it is preferable that it is selected from the group consisting of inhalable powders, dosing aerosols containing an aerosolizing gas and aerosol-free inhalation solutions.

Examples of compounds of general formula I are compounds selected from the group consisting of the following compounds:

6-hydroxy-8- (1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one;

6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid ethyl ester) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one;

6-hydroxy-8- (1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one;

8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one;

6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one;

PL 212 238 B1

8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-fluoro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (2,4-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (3,5-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-ethoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (3,5-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) ethylamino] -2- acid methylpropyl} phenoxy) butyric;

8- {2- [2- (3,4-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (2-chloro-4-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-chlorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-bromophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-fluoro-3-methoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-fluoro-2,6-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-chloro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-chloro-3-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-chloro-2-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (3-chloro-4-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- {2,6-difluoro-4-methoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (2,5-difluoro-4-methoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-fluoro-3,5-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (3,5-dichlorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (4-chloro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (3,4,5-trifluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one;

8- {2- [2- (3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one and

8- (2- [2- (3,4-dichlorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one.

The above-mentioned new compounds can exist in the form of individual optical isomers, mixtures of individual enantiomers or racemates. Especially these compounds can

Be in the form of enantiomerically pure compounds, the R-enantiomers of the compounds being of particular importance. The method of separating the racemates into the individual enantiomers is known from the prior art and can be used analogously to obtain enantiomerically pure R or S enantiomers of compounds of formula 1.

The compounds described above can exist in the form of addition salts with pharmacologically acceptable acids and, optionally, in the form of solvates and / or hydrates.

As addition salts with pharmacologically acceptable acids, for example, salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen phosphate, hydrogen methanesulfonate, hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen benzoate, hydrogen citrate, hydrogen fumarate, hydrogen tartrate, hydrogen tartrate, p-toluenesulfonate, preferably hydrochloride, hydrogen bromide, bisulfate, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulfonate.

Of the above-mentioned acid addition salts, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

When used according to the invention, the compounds of general formula I can optionally be used in the form of individual optical isomers, mixtures of individual enantiomers or racemates. If the compounds are introduced in enantiomerically pure form, the R enantiomers are preferably used.

As alkyl groups, unless otherwise stated, branched and unbranched alkyl groups with 1 to 4 carbon atoms are mentioned. Examples are methyl, ethyl, propyl or butyl. The abbreviations Me, Et, Prop or Bu are optionally used to designate methyl, ethyl, propyl or butyl groups. Unless otherwise stated, the definitions propyl and butyl include all possible isomeric forms of the residues in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, s-butyl and t-butyl, and the like.

As alkylene groups, unless otherwise stated, include branched and unbranched divalent alkyl bridges with 1 to 4 carbon atoms. Mention may be made, for example, of methylene, ethylene, n-propylene or n-butylene.

As alkyloxy groups (or also -O-alkyl groups), unless otherwise stated, branched and unbranched alkyl groups with 1 to 4 carbon atoms which are bonded via an oxygen atom are mentioned. By way of example, mention may be made of a methyloxy, ethyloxy, propyloxy or butyloxy group. The abbreviations MeO-, EtO-, PropO- or BuO- are also optionally used to denote methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, the definitions of propyloxy and butyloxy include all possible isomeric forms of the group in question. For example, propyloxy includes n-propyloxy and isopropyloxy, butyloxy includes isobutyloxy, s-butyloxy and t-butyloxy, and the like. The term alkoxy is also optionally used in place of the term alkyloxy in the context of the invention. Thus, the expressions methoxy, ethoxy, propoxy or butoxy are also optionally used to denote a methyloxy, ethyloxy, propyloxy or butyloxy group.

In the context of the invention, halogen may be mentioned as fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are mentioned as the preferred halogen unless otherwise stated.

The compounds of the invention can be prepared analogously to the methods described in the art. A suitable procedure is known, for example, from US Pat. No. 4,460,581, the contents of which are hereby incorporated by reference.

The examples below serve to illustrate more closely the compounds known in the art which compounds according to the invention can unexpectedly be used for the treatment of COPD.

Example 1. 6-Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-2,6-dimethylphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4 ] oxazin-3-one

ο.

OH

OH

This compound is known from US Pat. No. 4,460,581.

PL 212 238 B1

Example 2 8- {2- [1,1-dimethyl-3-phenylpropylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

This compound is known from US Pat. No. 4,460,581.

The synthesis examples below serve to illustrate the novel compounds of the invention in more detail. However, they are understood only as exemplary procedures for the explanation of the invention in more detail, without limiting the subject matter of the invention thereto.

Example 3. 6-Hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylethylamino] ethyl-

a) 8- {2- [1,1-dimethyl-2- (4-methoxyphenyl) ethylamino] -1-hydroxyethyl} -6-benzyloxy-4H-benzo [1,4] oxazin-3-one

7.5 g of glyoxal hydrate of 6-benzyloxy-4H-benzo [1,4] oxazine -3-one, and the mixture was stirred for 15 minutes. Then 1 g of sodium borohydride is added within 30 minutes at 10-20 ° C. The mixture is stirred for an hour, 10 ml of acetone are added and stirring is continued for 30 minutes. The reaction mixture is diluted with 150 ml of ethyl acetate, washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in 50 ml of methanol and 100 ml of ethyl acetate and acidified with concentrated hydrochloric acid. The product precipitates after the addition of 100 ml of diethyl ether. The crystals are filtered off, washed and recrystallized from 50 ml of ethanol. Yield: 7 g (68%, hydrochloride); melting point = 232-234 ° C.

b) 8- {2- [1,1-dimethyl-2- (4-methoxyphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

6.8 g of the benzyl compound obtained above in 125 ml of methanol were hydrogenated with the addition of 1 g of palladium on carbon (5%) at room temperature and under normal pressure. The catalyst is filtered off and the filtrate is freed from solvent. After recrystallization of the residue from 50 ml of acetone and a little water, a precipitate is obtained, which is filtered off and washed. Yield: 5.0 g (89%, hydrochloride); melting point = 155-160 ° C. The (R) and (S) enantiomers of Example 3 can be obtained from the racemate by, for example, chiral HPLC (e.g. Chirobiotic T column, 250 x 22.1 mm from Astec). Methanol with the addition of 0.05% triethylamine and 0.05% acetic acid can be used as the mobile phase. 5 µm silica gel to which the teicoplanin glycoprotein is covalently bonded can be used as the packing material for the column. Retention time (R-enantiomer) 40.1 minutes, retention time (S-enantiomer) 45.9 minutes. Both enantiomers are obtained by this method in the form of the free bases. According to the invention, the R-enantiomer of example 3 is of great importance.

Example 4. 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid ethyl ester) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazine- 3-on

PL 212 238 B1

a) 8- {2- [1,1-dimethyl-2- (4-phenoxyacetic acid ethyl ester) ethylamino] -1-hydroxyethyl} -6-benzyloxy-4H-benzo [1,4] oxazin-3-one

Analogously to the method described in example 3a) with 15 g of 6-benzyloxy-4H-benzo [1,4] oxazin-3-one glyoxal hydrate and 11.8 g of 1,1-dimethyl-2- hydrochloride (ethyl 4- acid). phenoxyacetic acid) of ethylamine affords the title compound. Yield: 16.5 g (69%, hydrochloride); melting point = 212-214 ° C.

b) 8- {2- [1,1-dimethyl-2- (4-phenoxyacetic acid ethyl ester) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one g the above-obtained benzyl alcohol is dissolved in 100 ml of ethanol, 100 ml of methanol and 10 ml of water and hydrogenated in the presence of 1 g of palladium on carbon (5%). After the theoretically calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was concentrated by evaporation. The product which crystallizes during the distillation of the solvent is suction filtered and washed. Yield: 5.5 g, hydrochloride); melting point = 137-140 ° C.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 5. 6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] -oxazin-3 -he

g 8- {2- [1,1-dimethyl-2- (4-phenoxyacetic acid ethyl ester) ethylamino] -1-hydroxyethyl} -6-benzyloxy-4H-benzo [1,4] oxazin-3-one hydrochloride ( Example 4a) is dissolved in 125 ml of methanol and hydrogenated in the presence of 1 g of palladium on carbon (5%). After the theoretically calculated amount of hydrogen has been taken up, the catalyst is filtered off. 2.6 g of sodium hydroxide dissolved in 20 ml of water are added to the filtrate. The mixture is refluxed for 30 minutes, methanol is distilled off and 10 ml of water, 20 ml of n-butanol and 3.9 ml of acetic acid are added. The precipitate formed is suction filtered and washed with diethyl ether. Yield: 7 g (87%). After recrystallization from 0.5 molar hydrochloric acid, the hydrochloride is obtained, m.p. = 152 ° C.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 6. 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] - oxazin-3-one

a) 1- (6-Benzyloxy-4H-benzo [1,4] oxazin-3-one) -2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylimino] ethanone

7.2 g of 6-benzyloxy-4H-benzo [1,4] oxazin-3-one glyoxal hydrate and 3.6 g of 1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamine are heated over a period of hours in 100 ml of ethanol to a temperature of 70 ° C. After cooling, the precipitated crystals are filtered off and washed with ethanol and diethyl ether. Performance:

8.6 g (94%); melting point = 175 ° C.

PL 212 238 B1

b) 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-benzyloxy-4H-benzo [1,4] -oxazin-3- he

8.6 g of Schiff's base obtained according to 6a) are dissolved in 100 ml of ethanol and 20 ml of THF, 0.7 g of sodium borohydride is added over 30 minutes at 10-20 ° C and the mixture is stirred for 1 hour. After adding 10 ml of acetone, stirring was continued for 30 minutes and then diluted with ethyl acetate and water. The product which crystallizes upon acidification with concentrated hydrochloric acid is filtered off and washed. Yield: 7.4 g (80%, hydrochloride); melting point = 235 DEG C. (decomposition).

c) 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

7.4 g of the benzyl compound obtained in b) in 125 ml of methanol with the addition of 1 g of palladium on carbon (5%) are hydrogenated at room temperature and under normal pressure. The product which crystallizes after adding acetone is suction filtered and washed with acetone and diethyl ether. Yield: 5 g (78%, hydrochloride); mp 160 DEG C. (decomposition).

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 7. 6-Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one

a) 8- {2- [1,1-dimethyl-2- (4-hydroxyphenyl) ethylamino] -1-hydroxyethyl} -6-benzyloxy-4H-benzo [1,4] oxazin-3-one

The title compound is prepared from 10 g of 6-benzyloxy-4H-benzo [1,4] oxazin-3-one glyoxal hydrate and 4.6 g of 1,1-dimethyl-2- (4-hydroxyphenyl) ethylamine by analogy to Example 3a) . Yield: 9.0 g (64%, hydrochloride); melting point = 255-258 ° C.

b) 8- {2- [1,1-dimethyl-2- (4-hydroxyphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

5.7 g of the coupling product obtained above are hydrogenated in the presence of 0.6 g of palladium on carbon (5%) in 100 ml of methanol. After the theoretically calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is freed of the solvent. The residue is dissolved in ethanol under heating and then combined with diethyl ether. The precipitated product is suction filtered and recrystallized once from water. Yield: 3.6 g (72%, hydrochloride); melting point = 159-162 ° C.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 8. 6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3- he

a) 1- (4-Isopropylphenyl) -2-methylpropan-2-ol

By reacting the Grignard compound prepared from 20 g (119 mmol) of 4-isopropylbenzyl chloride with 11.4 ml (155 mmol) of acetone, the target compound is obtained in the form of a colorless oil. Yield: 13.0 g (57%); mass spectrometry: [M + H] ⁺ = 193.

PL 212 238 B1

b) N- [2- (4-Isopropylphenyl) -1,1-dimethylethyl] acetamide

A Ritter reaction is performed using 10.2 g (53 mmol) of 1- (4-isopropylphenyl) -2-methylpropan-2-ol as described in example 9b). The reaction mixture was poured into ice-water and made basic with sodium hydroxide solution and a precipitate formed. The sludge is sucked off and dried. Yield: 9.90 g (80%); mass spectrometry: [M + H] ⁺ = 234.

c) 2- (4-Isopropylphenyl) -1,1-dimethylethylamine

In analogy to Example 9c), 9.80 g (42 mmol) of N- [2- (4-isopropylphenyl) -1,1-dimethylethyl] acetamide are reacted. Yield: 7.00 g (71%, hydrochloride); mp 202-206 ° C.

d) 6-Benzyloxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one

2.18 g (6.1 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1.4] oxazin-3-one and 1.1 g (5.8 mmol) of 2- (4-isopropylphenyl) -1,1-dimethylethylamine is stirred for one hour at 50-80 ° C in 40 ml of ethanol. After cooling to room temperature, 0.24 g (6.3 mmol) of sodium borohydride are added. The mixture was stirred for an hour, diluted with 5 ml of acetone and the mixture was stirred for a further 30 minutes. The reaction mixture is acidified with hydrochloric acid, 100 ml of water and 80 ml of ethyl acetate are added and the mixture is made basic with ammonia. The organic phase is separated, dried over sodium sulphate and freed from the solvent. The residue is dissolved in 20 ml of ethyl acetate and 10 ml of water, acidified with concentrated hydrochloric acid and diluted with diethyl ether. A crystallization aid is added, then the precipitate is suction filtered and washed. A white solid is obtained. Yield: 1.7 g (52%, hydrochloride); mp 220-222 ° C.

e) 6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one

1.6 g (3.0 mmol) 6-benzyloxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1.4] oxazin-3-one is dissolved in methanol and hydrogenated with palladium on carbon as a catalyst at normal pressure and room temperature. The catalyst is sucked off, the solvent is distilled off and the residue is recrystallized from isopropanol to give a white solid. Yield: 1.1 g (85%, hydrochloride); mp 248-250 ° C; mass spectrometry: [M + H] ⁺ = 399.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 9. 8- {2- [2- (4-Ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-

a) 1- (4-Ethylphenyl) -2-methylpropan-2-ol

14.8 g (90 mmol) of 1- (4-ethylphenyl) propan-2-one dissolved in diethyl ether are added dropwise to 39 ml of a 3-molar solution of methylmagnesium bromide in diethyl ether while cooling in an ice bath in such a way that the temperature it did not exceed 30 ° C. After the addition is complete, the reaction mixture is refluxed for 1.5 hours and then hydrolysed with 10% ammonium chloride solution. After separating off the organic phase, the aqueous phase is extracted with diethyl ether. The combined ether phases are washed with water, dried over sodium sulphate and evaporated down. The oil thus obtained is directly reacted further. Yield: 15.5 g (90%).

b) N- [2- (4-Ethylphenyl) -1,1-dimethylethyl] acetamide

To 15.5 g (87 mmol) of 1- (4-ethylphenyl) -2-methylpropan-2-ol in 4.8 ml (91 mmol) of acetonitrile and 15 ml of glacial acetic acid are added dropwise 6.2 ml over 15 minutes. concentrated sulfuric acid, the temperature rising to 65 ° C. The mixture was then stirred for an hour, diluted with ice water and made basic with concentrated sodium hydroxide solution. Stirring was continued for 30 minutes, then the precipitate formed was suction filtered and washed with water. The crude product dissolves

The mixture was washed with ethyl acetate, dried over sodium sulfate and concentrated. Petroleum ether is added to the oil obtained and a precipitate is formed which is filtered off and dried. Yield: 16.3 g (85%); mp 90-92 ° C.

c) 2- (4-Ethylphenyl) -1,1-dimethylethylamine

16.3 g (74 mmol) of N- [2- (4-ethylphenyl) -1,1-dimethylethyl] acetamide and 8.0 g of potassium hydroxide are refluxed for 15 hours in 60 ml of ethylene glycol . Ice water is added to the reaction mixture, and the mixture is extracted three times with diethyl ether. The combined organic phases are washed with water, dried over sodium sulphate and freed from the solvent. To obtain the hydrochloride, the crude product was dissolved in acetonitrile and ethereal hydrochloric acid solution and diethyl ether were successively added. The resulting precipitate is suction filtered and dried. Yield: 11.0 g (69%, hydrochloride); mp 165-167 ° C.

d) 6-Benzyloxy-8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

The target compound is prepared analogously to example 8d) from 2.14 g (6.0 mmol) of 6-benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 1.0 g (5.6 mmol) of 2- (4-ethylphenyl) -1,1-dimethylethylamine to give a white solid. Yield: 1.7 g (54%, hydrochloride); mp 210-214 ° C.

e) 8- {2- [2- (4-Ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

1.45 g (2.75 mmol) of 6-benzyloxy-8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1.4 ] oxazin-3-one according to Example 8e), the target compound is obtained in the form of a white solid. Yield: 1.07 g (92%, hydrochloride); mp 266-269 ° C; mass spectrometry: [M + H] ⁺ = 385.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 10. 8- {2- [2- (4-Fluoro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on

ο.

OH

a) 1-Fluoro-2-methyl-4- (2-methylpropenyl) benzene

To 100 ml of a 0.5 molar solution of 4-fluoro-3-methylphenylmagnesium bromide in THF, 4.7 ml (50 mmol) of isopropyl aldehyde are added over 30 minutes, with the temperature rising to 45 ° C. The mixture was stirred for 30 minutes, refluxed for 1 hour, then hydrolyzed with 10% ammonium chloride solution. After separating off the organic phase, it is extracted with diethyl ether. The organic phases are combined, dried and concentrated. The alcohol thus obtained was dissolved in 100 ml of toluene, 1 g of p-toluenesulfonic acid monohydrate was added and the mixture was heated for 3 hours with a water separator. The reaction mixture was poured into water and made basic with concentrated sodium hydroxide solution. After the organic phase has been separated, it is washed with water, dried over sodium sulphate and freed from solvent. After fractionated distillation of the residue, the product is obtained in the form of a colorless liquid (bp 80-85 ° C / 10 mbar). Yield: 4.1 g (50%).

b) N- [2- (4-Fluoro-3-methylphenyl) -1,1-dimethylethylformamide

4.9 ml of concentrated sulfuric acid are added dropwise to 1.5 g (31 mmol) of sodium cyanide in 5 ml of glacial acetic acid at 5-15 ° C. Then 3.9 g (24 mmol) of 1-fluoro-2-methyl-4- (2-methylpropenyl) benzene dissolved in 10 ml of glacial acetic acid are added to the mixture and the mixture is stirred for 1 hour at 50-60 ° C. C. The reaction mixture is diluted with ice water, made basic with concentrated sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulphate and freed from the solvent under reduced pressure. The slightly yellow oil thus obtained was directly reacted further. Performance:

4.3 g (87%).

PL 212 238 B1

c) 2- (4-Fluoro-3-methylphenyl) -1,1-dimethylethylamine

4.3 g (20.6 mmol) of N- [2- (4-fluoro-3-methylphenyl) -1,1-dimethylethyl] formamide, 20 ml of concentrated hydrochloric acid and 20 ml of water are refluxed. in 2 hours. The reaction mixture is diluted with water, made basic with concentrated sodium hydroxide solution and extracted with dichloromethane. The organic phases are dried over sodium sulfate and evaporated down. The residue was dissolved in ethyl acetate, ethereal hydrochloric acid was added and cooled. The precipitated crystals are suction filtered and washed with diethyl ether and dried. A white solid is obtained. Yield: 3.9 g (87%, hydrochloride); mp 196-198 ° C.

d) 6-Benzyloxy-8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

1.10 g (3.1 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1.4] oxazin-3-one and 0.50 g (2.8 mmol) of 2- (4-fluoro-3-methylphenyl) -1,1-dimethylethylamine was reacted analogously to Example 8d and further reacted. A white solid is obtained. Yield: 0.75 g (47%, hydrochloride); mp 228-230 ° C.

e) 8- {2- [2- (4-Fluoro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

As a result of hydrogenation 0.70 g (1.4 mmol) of 6-benzyloxy-8- {2- [2- (4-fluoro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] Oxazin-3-one gives the target compound as a white solid. Yield: 0.50 g (87%, hydrochloride); mp 278-280 ° C; mass spectroscopy: [M + H] ⁺ = 389.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 11. 8- {2- [2- (4-Fluoro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on

ο.

OH

a) Acetic acid 1- (4-fluoro-2-methylphenyl) -2-methylpropyl ester

500 ml of a 0.5 M solution of 4-fluoro-6-methylphenylmagnesium bromide and 23.2 ml (260 ml) of isopropyl aldehyde are reacted analogously to example 10a). After hydrolysis with 10% ammonium chloride solution, the aqueous phase is separated and extracted with diethyl ether. The combined organic phases are dried over sodium sulfate and concentrated. The alcohol thus obtained was then dissolved in 50 ml of acetic anhydride, 1 ml of concentrated sulfuric acid was added and the mixture was stirred and refluxed for 3 hours. The reaction mixture was then poured into water, stirred for a further hour and made basic. It is extracted with dichloromethane, the organic phases are dried over sodium sulphate and the solvent is distilled off. The residue is fractionally distilled to give the product as a colorless liquid (bp 105-110 ° C / 8 mbar). Yield: 29.0 g (52%).

b) N- [2- (4-Fluoro-2-methylphenyl) -1,1-dimethylethyl] formamide

29.0 g (130 mmol) of acetic acid 1- (4-fluoro-2-methylphenyl) -2-methylpropyl ester were reacted analogously to example 10b) and worked up. A yellow oil is obtained. Yield: 27.0 g (99%).

c) 2- (4-Fluoro-2-methylphenyl) -1,1-dimethylethylamine To obtain the amine 27.0 g (130 mmol) N- [2- (4-fluoro-2-methylphenyl) -1.1- dimethylethyl] -formamide is reacted according to example 10c). A white solid is obtained. Yield: 15.5 g (55%, hydrochloride); mp 277-280 ° C.

d) 6-Benzyloxy-8- {2- [2- (4-fluoro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

This compound is prepared analogously to example 8d) from 0.95 g (2.66 mmol) of benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 0, 43 g (2.37 mmol) of 2- (4-fluoro-2-me14

PL 212 238 B1 phenyl) -1,1-dimethylethylamine. Yield: 0.75 g (55%, hydrochloride); mp 233-236 ° C.

e) 8- {2- [2- (4-Fluoro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

By debenzylation, 0.70 g (1.36 mmol) of 6-benzyloxy-8- {2- [2- (4-fluoro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] Oxazin-3-one gives the target compound as a white solid. Yield: 0.50 g (87%, hydrochloride); mp 278-280 ° C; mass spectroscopy: [M + H] ⁺ = 389.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 12. 8- {2- [2- (2,4-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3- he

ο.

'F

OH

a) 1- (2,4-Difluorophenyl) -2-methylpropan-2-ol

To 500 ml of a 0.25-molar solution of 2,4-difluorobenzylmagnesium bromide in diethyl ether, 11.0 ml of acetone diluted with 50 ml of diethyl ether are added dropwise over 20 minutes. The mixture was heated to reflux for 1.5 hours while stirring and then hydrolysed with 10% ammonium chloride solution. The ethereal phase is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation. After fractional distillation of the residue, the alcohol is obtained in the form of a colorless liquid (bp 70-73 ° C / 2 mbar). Yield: 20.0 g (86%).

b) N- [2- (2,4-Difluorophenyl) -1,1-dimethylethyl] formamide g (110 mmol) 1- (2,4-difluorophenyl) -2-methylpropan-2-ol are subjected to the Ritter reaction according to the example 10b). A yellow oil is obtained. Yield: 22.0 g (94%).

c) 2- (2,4-Difluorophenyl) -1,1-dimethylethylamine

22.0 g (100 mmol) of N- [2- (2,4-difluorophenyl) -1,1-dimethylethyl] formamide are reacted analogously to Example 10c). Yield: 16.0 g (72%, hydrochloride); mp 201-203 ° C.

d) 6-Benzyloxy-8- {2- [2- (2,4-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

0.89 g (2.49 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1.4] oxazin-3-one and 0.40 g (2.16 mmol) of 2- (2,4-difluorophenyl) -1,1-dimethylethylamine is reacted as described in Example 8d). Yield: 0.80 g (62%, hydrochloride); mp 245-247 ° C.

e) 8- {2- [2- (2,4-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

By hydrogenolysis, 0.70 g (1.35 mmol) of 6-benzyloxy-8- {2- [2- (2,4-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1 , 4] oxazin-3-one, the target compound is obtained as a white solid. Yield: 0.48 g (83%, hydrochloride); mp 279-280 ° C; mass spectroscopy: [M + H] ⁺ = 393.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 13. 8- {2- [2- (3,5-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazine-3- he

ABOUT.

OH

PL 212 238 B1

a) 1- (3,5-Difluorophenyl) -2-methylpropan-2-ol

The target compound is obtained by reacting the Grignard compound prepared from 25.0 g (121 mmol) of 3,5-difluorobenzyl bromide with 12.6 ml (171 mmol) of acetone. A yellow oil is obtained. Yield: 13.5 g (60%).

b) 2- (3,5-Difluorophenyl) -1,1-dimethylethylamine

5.5 g (29.5 mmoles) of 1- (3,5-difluorophenyl) -2-methylpropan-2-ol and 1.8 g of sodium cyanide are subjected to a Ritter reaction to give 7.0 g of formamide which is cleaved off the formyl group is treated with hydrochloric acid. A slightly yellow oil is obtained. Yield: 4.6 g (75%).

c) 6-Benzyloxy-8- {2- [2- (3,5-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

This compound is prepared from 1.73 g (4.84 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 0.80 g (4 , 32 mmol) 2- (3,5-difluorophenyl) -1,1-dimethylethylamine in a known manner. Yield: 1.50 g (58%, hydrochloride); mp 240-244 ° C.

d) 8- {2- [2- (3,5-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

1.30 g (2.43 mmol) of 6-benzyloxy-8- {2- [2- (3,5-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1.4 ] oxazin-3-one gives the target compound as a white solid. Yield: 0.90 g (86%, hydrochloride); mp 150-158 ° C; mass spectroscopy: [M + H] ⁺ = 393.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 14. 8- {2- [2- (4-Ethoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

a) [2- (4-Ethoxyphenyl) -1,1-dimethylethyl] carbamic acid benzyl ester

15.0 g (50 mmol) of [2- (4-hydroxyphenyl) -1,1-dimethylethyl] carbamic acid benzyl ester is mixed with 7.5 ml (92 mmol) of ethyl iodide and 21 g (150 mmol) of potassium carbonate in for 10 hours at 90-100 ° C. The reaction mixture was treated with ethyl acetate, washed twice with water and dried over sodium sulfate. After distilling off the solvent, a yellow oil (15.0 g, 92%) was obtained which was directly reacted further.

b) 2- (4-Ethoxyphenyl) -1,1-dimethylethylamine

To a solution of 15.0 g (49 mmol) of [2- (4-ethoxyphenyl) -1,1-dimethylethyl] carbamic acid benzyl ester in 100 ml of glacial acetic acid, 2 g of palladium on carbon (10%) are added and then hydrogenated at 5 bar pressure and 40-50 ° C. The catalyst is filtered off and the filtrate is freed from the solvent. The residue was dissolved in a little water, made basic with concentrated sodium hydroxide solution and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated down. The crude product was dissolved in acetonitrile and acidified with ethereal hydrochloric acid. After adding diethyl ether, the precipitate is suction filtered and dried. Yield: 8.8 g (hydrochloride, 84%); mp 198-200 ° C.

c) 6-Benzyloxy-8- {2- [2- (4-ethoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

2.14 g (6.0 mmol) of 6-benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 1.0 g (5.2 mmol) 2- (4-ethoxyphenyl) -1,1-dimethylethylamine is stirred in 40 ml of ethanol for one hour at 50-80 ° C. After cooling to room temperature, 0.23 g (6.0 mmol) of sodium borohydride is added and the mixture is stirred for a further hour. 5 ml of acetone are added to the mixture, it is stirred for 30 minutes, acidified with glacial acetic acid and evaporated down. Water and ethyl acetate are added to the residue and made alkaline. The organic phase is separated and washed

The mixture is dried over sodium sulphate and freed from the solvent under reduced pressure. The residue was redissolved in ethyl acetate and water, concentrated hydrochloric acid was added and diluted with diethyl ether. The precipitate formed is suction filtered and washed with diethyl ether. A white solid is obtained. Yield: 2.0 g (61%, hydrochloride); mp 214-216 ° C.

d) 8- {2- [2- (4-Ethoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

1.5 g (2.8 mmol) 6-benzyloxy-8- {2- [2- (4-ethoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] -oxazines -3-one in 80 ml of methanol is hydrogenated in the presence of 250 mg of palladium on carbon (10%) as a catalyst at room temperature and normal pressure. The catalyst was sucked off and the filtrate was concentrated. The residue is dissolved with heating in 5 ml of ethanol, seeded and diluted with ethyl acetate. The precipitate formed is filtered off and washed. A white solid is obtained. Yield: 1.0 g (83%, hydrochloride); mp 232-235 ° C; mass spectrometry: [M + H] ⁺ = 401.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 15. 8- {2- [2- (3,5-Dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3- he

a) 1- (3,5-Dimethylphenyl) -2-methylpropanol-2-ol

This compound is obtained by reacting (3,5-dimethylphenyl) acetic acid ethyl ester with methylmagnesium bromide.

b) 2- (3,5-Dimethylphenyl) -1,1-dimethylethylamine

By the reaction of 6.00 g (34 mmol) of 1- (3,5-dimethylphenyl) -2-methylpropanol-2-ol and 2.00 g (41 mmol) of sodium cyanide by the Ritter reaction, 2.40 g of 2- ( 3,5-dimethylphenyl) -1,1-dimethylethylformamide (35% yield). Formamide (2.40 g, 11.7 mmol) is treated with hydrochloric acid to liberate the amine. Carrying out the reaction and working-up is analogous to example 10c). An oil is obtained. Yield: 1.70 g (82%); mass spectroscopy: [M + H] ⁺ = 178.

c) 6-Benzyloxy-8- {2- [2- (3,5-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H-benzo [1,4] oxazin-3-one

This compound is prepared analogously to Example 8d) from 1.47 g (4.1 mmol) of benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 0, 65 g (3.7 mmol) of 2- (3,5-dimethylphenyl) -1,1-dimethylethylamine. Yield: 1.1 g (51%, hydrochloride); mp 220-222 ° C.

d) 8- {2- [2- (3,5-Dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

The target compound is obtained by hydrogenolysis of 0.90 g (1.71 mmol) 6-benzyloxy-8- {2- [2- (3,5-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -4H- benzo [1,4] oxazin-3-one and recrystallization of the crude product from isopropanol. A white solid is obtained. Yield: 0.50 g (69%, hydrochloride); mp 235-238 ° C; mass spectroscopy: [M + H] ⁺ = 385.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 16 Acid 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] -oxazin-8-) yl) ethylamino] -2-methylpropyl} phenoxy) butyric

PL 212 238 B1

a) 4- [4- (2-amino-2-methylpropyl) phenoxy] butyric acid ethyl ester

4.5 g (15.0 mmol) [2- (4-hydroxyphenyl) -1,1-dimethylethyl] carbamic acid benzyl ester, 2.3 ml (16.0 mmol) 4-bromobutyric acid ethyl ester, 2.3 g (16.6 mmol) of potassium carbonate and 0.3 g (1.8 mmol) of potassium iodide in 20 ml of dimethylformamide were heated to 120 ° C. for 13 hours. The reaction mixture is diluted with ethyl acetate and washed successively with water, sodium hydroxide solution and water. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by chromatography (eluent: cyclohexane / ethyl acetate = 9: 1). 5.0 g of a yellow oil are obtained, dissolved in 50 ml of acetic acid and hydrogenated in the presence of 1.0 g of palladium-on-carbon catalyst at a temperature of 40 DEG C. and a pressure of 3 bar. The catalyst is filtered off and the filtrate is freed from the solvent. The residue is dissolved in diethyl ether and combined with ethereal hydrochloric acid. The resulting precipitate is suction filtered and dried. Yield: 2.9 g (66% over 2 steps, hydrochloride); mp 103-105 ° C.

b) 4- (4- {2- [2- (6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -2-hydroxyethylamino] acid ethyl ester] -2-methylpropyl} phenoxy) butyric

1.20 g (3.36 mmol) benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 0.90 g (3.22 mmol) ethyl ester 4- [4- (2-amino-2-methylpropyl) phenoxy] butyric acid is reacted as described in example 8d). The crude product is dissolved in 10 ml of ethyl acetate and 10 ml of water and oxalic acid is added with stirring. The solution is diluted with diethyl ether and the precipitate formed is suction filtered and washed with diethyl ether. Yield: 1.20 g (54%, oxalate); mp 223-227 ° C.

c) 4- (4- {2- [2- (6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -2-hydroxyethylamino] -2 -methylpropyl} phenoxy) butyric

To a solution of 1.00 g (1.73 mmol) of 4- (4- {2- [2- (6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazines) -8-yl) -2-hydroxyethylamino] -2-methylpropyl} phenoxy) butyric acid in 25 ml of methanol is introduced with 2.5 ml of 1N sodium hydroxide solution, refluxed for 30 minutes and then neutralized. 1N hydrochloric acid. The solution was concentrated and the resulting oil was dissolved in 5 ml of n-butanol with heating. After the addition of a crystallization aid, a precipitate formed, which was suction filtered and washed with acetone and diethyl ether. Yield: 0.75 g (79%); mp 216-218 ° C.

d) 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] acid -2-methylpropyl} phenoxy) butyric

0.70 g (1.28 mmol) 4- (4- {2- [2- (6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) acid ) -2-hydroxyethylamino] -2-methylpropyl} phenoxy) butyric acid is dissolved in 25 ml of methanol and 2 ml of acetic acid and hydrogenated in the presence of 150 mg of palladium on carbon (10%) at room temperature and normal pressure. The catalyst is filtered off and the filtrate is freed from the solvent. The product is obtained by crystallization from a methanol / acetone mixture. Yield: 0.40 g (68%); mp 201-204 ° C; mass spectroscopy: [M + H] ⁺ = 459.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 17. 8- {2- [2- (3,4-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3- he

a) 1- (3,4-Difluorophenyl) -2-methylpropan-2-ol

Grignard is prepared from 23.0 g (111 mmol) of 3,4-difluorobenzyl bromide, which is then reacted with 11.6 ml (158 mmol) of acetone. A slightly yellow oil is obtained. Performance:

9.7 g (47%); Rf value: 0.55 (ethyl acetate / petroleum ether = 1: 3).

PL 212 238 B1

b) N- [2- (3,4-Difluorophenyl) -1,1-dimethylethyl] formamide

The target compound is obtained by Ritter reaction with 4.0 g (21.5 mmol) of 1- (3,4-difluorophenyl) -2-methylpropan-2-ol. A slightly yellow oil is obtained. Yield: 4.0 g (87%); mass spectrometry: [M + H] ⁺ = 214.

c) 2- (3,4-Difluorophenyl) -1,1-dimethylethylamine

4.00 g (18.5 mmol) of N- [2- (3,4-difluorophenyl) -1,1-dimethylethyl] formamide are dissolved in ethanol, concentrated hydrochloric acid is added and the mixture is refluxed. night. The reaction solution is poured into ice-water, made basic with sodium hydroxide and extracted with t-butyl methyl ether. The organic phases are washed with water, dried over sodium sulphate and evaporated down. A yellow oil is obtained. Yield: 3.2 g (92%); mass spectrometry: [M + H] ⁺ = 186.

d) 8- {2- [2- (3,4-Difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

357 mg (1 mmol) 6-benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 185 mg (1 mmol) 2- (3,4-difluorophenyl) ) -1,1-dimethylethylamine is stirred for 30 minutes in 5 ml of tetrahydrofuran at room temperature. The mixture is cooled to 0 ° C. and 1.5 ml of a 2-molar solution of lithium borohydride in tetrahydrofuran are added dropwise under argon. The mixture was stirred for 30 minutes at room temperature, 10 ml of dichloromethane and 3 ml of water is stirred _® for a further hour, then filtered through Extrelut ^®. The ethanolamine-containing eluate is free of solvent. The residue is dissolved in methanol and hydrogenated in the presence of palladium on carbon (10%) as a catalyst at 2.5 bar pressure and room temperature. The catalyst is then separated off and the crude product is purified by chromatography. A white solid is obtained. Yield: 31 mg (6%, trifluoroethylacetate); mass spectroscopy: [M + H] ⁺ = 393.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 18 8- {2- [2- (2-Chloro-4-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on

ο.

OH

a) 1- (2-Chloro-4-fluorophenyl) -2-methylpropan-2-ol

This compound is prepared from 20 g (97 mmol) of (2-chloro-4-fluorophenyl) -acetic acid methyl ester and 98 ml of a 3-molar solution of methylmagnesium bromide by analogy to Example 8a).

b) N- [2- (2-Chloro-4-fluorophenyl) -1,1-dimethylethyl] formamide

7.5 g (37 mmol) of 1- (2-chloro-4-fluorophenyl) -2-methylpropan-2-ol are reacted and worked up as described in example 10b). The oil thus obtained was further purified by chromatography on a short silica gel column (petroleum ether / ethyl acetate = 9: 1). An oil is obtained. Yield 7.4 g (87%); mass spectrometry: [M + H] ⁺ = 230/232.

c) 2- (2-Chloro-4-fluorophenyl) -1,1-dimethylethylamine

7.4 g (32 mmol) of N- [2- (2-chloro-4-fluorophenyl) -1,1-dimethylethyl] formamide are reacted as described in example 17c). A brown oil is obtained. Yield: 5.14 g (79%); mass spectrometry: [M + H] ⁺ = 202/204.

d) 8- {2- [2- (2-Chloro-4-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazine 3-one

357 mg (1 mmol) 6-benzyloxy-8- (2-ethoxy-2-hydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 202 mg (1 mmol) 2- (2-chloro-4) -fluorophenyl) -1,1-dimethylethylamine is reacted with lithium borohydride in analogy to Example 10d). For the depenzylation of the ethanolamine thus obtained, the compound was dissolved in 3 ml of dichloromethane and cooled to -78 ° C. At this temperature, 2 ml of a 1M solution of boron tribromide in dichloromethane are added dropwise and allowed to warm slowly to room temperature. To the reaction mixture was added 10 ml of dichloromethane and 3 ml of water _® and filtered through Extrelut ^®. The eluate is freed from solvent and the residue is purified

By chromatography. A white solid is obtained. Yield: 70 mg (13%, trifluoroethylacetate); mass spectroscopy: [M + H] ⁺ = 409/11.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 19 8- {2- [2- (4-Chlorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydro-

For a solution of 300 mg (0.91 mmol) of 6-benzyloxy-8- (2,2-dihydroxyacetyl) -4H-benzo [1,4] -oxazin-3-one and 200 mg (1.09 mmol) of 2- ( A molecular sieve is introduced into 4-chlorophenyl) -1,1-dimethylethylamine in 3 ml of ethanol and the mixture is stirred for 90 minutes at 80 ° C. The mixture is allowed to cool to room temperature, 35 mg (0.91 mmol) of sodium borohydride are added and the mixture is stirred for 1 hour. Then, a sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were freed from solvent and the residue was chromatographed (eluent: hexane / ethyl acetate / methanol) to give 305 mg of ethanolamine. This compound was dissolved in 3 ml of dichloromethane and cooled to -78 ° C under argon. 3 ml of a 1-molar solution of boron tribromide in dichloromethane are added dropwise and the mixture is stirred for one hour at -78 ° C and for 20 minutes at room temperature. Then, at -78 ° C, 3 ml of concentrated ammonia solution were added dropwise and the mixture was stirred for 5 minutes. Ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases are concentrated and the residue is chromatographed (silica gel, eluent: dichloromethane / methanol + 1% ammonia) for further purification. A beige solid is obtained: 93 mg (26%); mass spectrometry: [M + H] ⁺ = 391.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 20 8- {2- [2- (4-Bromophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

Ethanolamine production and depenzylation were carried out as described in Example 19 using 300 mg (0.91 mmol) of 6-benzyloxy-8- (2,2-dihydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 250 mg (1.09 mmol) of 2- (4-bromophenyl) -1,1-dimethylethylamine. A beige solid is obtained. Yield: 54 mg (14%); mass spectrometry: [M + H] ⁺ = 435,437.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

Example 21 8- {2- [2- (4-Fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

PL 212 238 B1

300 mg (0.91 mmol) of 6-benzyloxy-8- (2,2-dihydroxyacetyl) -4H-benzo [1,4] oxazin-3-one and 183 mg (1.09 mmol) of 2- (4-fluorophenyl) ) -1,1-dimethylethylamine is dissolved in 3 ml of ethanol. A molecular sieve is introduced and the mixture is stirred for 30 minutes at 80 ° C. After cooling to room temperature, 35 mg (0.91 mmol) of sodium borohydride are added. After the mixture was stirred for 1 hour at room temperature, sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phases are concentrated and the residue is chromatographed (eluent: hexane / ethyl acetate / methanol). So obtained, ethanolamine (223 mg) to cleave the benzyl protecting group is dissolved in methanol and hydrogenated in the presence of 150 mg palladium hydroxide as a catalyst at room temperature and under nor mal _® pressure. The catalyst was separated by filtration through Celite ^®, the filtrate was freed from solvent and the residue chromatographed (silica gel; eluent: dichloromethane / methanol). A beige solid is obtained. Yield: 76 mg (22%); mass spectrometry: [M + H] ⁺ = 375.

The (R) and (S) enantiomers in this example can be obtained by racemate resolution analogously to the usual art-known methods for cleaving racemates.

The following compounds of the formula I according to the invention can also be prepared analogously to the above synthesis examples.

Example 22 8- {2- [2- (4-Fluoro-3-methoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on.

Example 23. 8- {2- [2- (4-Fluoro-2,6-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one.

Example 24 8- {2- [2- (4-Chloro-2-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on.

Example 25 8- {2- [2- (4-Chloro-3-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on,

Example 26 8- {2- [2- (4-Chloro-2-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on.

Example 27.8- {2- [2- (3-Chloro-4-fluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3 -he.

Example 28. 8- {2- [2- (2,6-Difluoro-4-methoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one.

Example 29 8- {2- [2- (2,5-Difluoro-4-methoxyphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one.

Example 30 8- {2- [2- (4-Fluoro-3,5-dimethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4 ] oxazin-3-one.

Example 31 8- {2- [2- (3,5-Dichlorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3 -he.

Example 32 8- {2- [2- (4-Chloro-3-methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on.

Example 33 8- {2- [2- (3,4,5-Trifluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines -3-on.

Example 34. 8- {2- [2- (3-Methylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazines 3-one.

Example 35 8- {2- [2- (3,4-Dichlorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3- he.

The compounds of general formula I can be used according to the invention alone or in combination with other active compounds of formula 1 according to the invention. The compounds of general formula I can, if appropriate, also be used in combination with further pharmacologically active substances. Mention may be made in particular of anticholinergic substances, possibly other betamimetic and antiallergic substances, PDE IV inhibitors, PAF antagonists, leukotriene antagonists and corticosteroids and combinations of these active substances.

Preferred examples of anticholinergic substances are the ipratropium, oxitropy and tiotropium salts. Combinations of medicaments which contain the abovementioned salts in addition to the compounds of the formula I according to the invention preferably contain ipatropic, oxitropic or tiotropium salts in which the anion is selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate. , nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, optionally in the form of solvates or hydrates.

Within the scope of the invention, corticosteroids which can optionally be used in combination with a compound of formula I are compounds selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, cyclesonide, rofleponide and dexamethasone. In the present specification, only the term steroids is also used in place of the term corticosteroids. Reference to steroids according to the invention also includes salts or derivatives which can be formed from the steroids. Possible salts or derivatives are, for example, sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitate, pivalates or furanecarboxylates. Corticosteroids can also be in the form of hydrates.

Within the scope of the invention, dopamine agonists which can optionally be used in combination with a compound of formula I include compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexol, terguride and caravan. Within the scope of the invention, reference to the abovementioned dopamine agonists also includes their possibly occurring pharmacologically acceptable acid addition salts and, if appropriate, their hydrates. Among the physiologically acceptable acid addition salts which can be formed with the abovementioned dopamine agonists are, for example, pharmaceutically acceptable salts selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

Examples of antiallergic substances which can be used according to the invention in combination with a compound of the formula I are epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bipheryramine, cexylchloraminiphene, cexylchloraminiphene, cexylchloramine. , chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclosine. Within the scope of the invention, a reference to the abovementioned antiallergic substances also includes their possibly occurring pharmacologically acceptable acid addition salts.

Examples of PDE-IV inhibitors which can be used in combination with a compound of formula 1 according to the invention are compounds selected from the group consisting of enprophyllin, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch- 351591), V-11294A and AWD-12-281. Any reference to the abovementioned PDE-IV inhibitors within the scope of the invention also includes their possibly occurring pharmacologically acceptable acid addition salts. Among the physiologically acceptable acid addition salts which can be formed with the abovementioned PDE-IV inhibitors, suitable are pharmaceutically acceptable salts selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. According to the invention, salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred.

Suitable dosage forms for the administration of the compounds of the formula I are, for example, tablets, capsules, suppositories, solutions, powders and the like. The proportion of pharmaceutically active compounds should in each case be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight. by weight of the total composition. Suitable tablets can be prepared, for example, by mixing one or more active ingredients with known excipients, such as, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrating agents such as corn starch or alginic acid, binders such as starch. or gelatin, lubricants such as magnesium stearate or talc and / or agents for a prolonged effect such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of several layers.

Accordingly, it is also possible to prepare dragees by coating cores obtained analogously to the tablets with agents conventionally used for coating dragees, such as, for example, collidone or shellac, acacia, talc, titanium dioxide or sugar. In order to obtain the effect of prolonged operation or to avoid incompatibility, the nucleus may also consist of several layers. Similarly, the dragee coating may consist of several layers in order to obtain the effect of prolonged action, and the excipients mentioned above for discussing the tablets may be used.

PL 212 238 B1

Juices containing the active substances according to the invention or the active compound combinations may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerin or sugar, and a taste improving agent, for example flavoring substances, such as vanillin or orange extract. They may furthermore contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoates.

The solutions are prepared in a known manner, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, optionally with the use of emulsifying and / or dispersing agents, for example when water is used as of the diluent, organic solvents can optionally be used as solubilizers or as auxiliary solvents. These solutions are filled into injection bottles or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as milk sugar or sorbitol and enclosing them in gelatine capsules.

Suitable suppositories may, for example, be prepared by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.

Excipients used are, for example, water, pharmaceutically acceptable organic solvents, such as paraffin (e.g. petroleum fractions), oils of vegetable origin (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers, such as e.g. natural mineral meals (e.g. kaolins, clays, talc, chalk), synthetic mineral meals (e.g. highly dispersible silicic acid and silicates), sugars (e.g. cane, milk and grape sugar), emulsifying agents (e.g., lignin, sulphite liquors, methylcellulose, starch, and polyvinylpyrrolidone); and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

When used orally, tablets may of course also contain additives such as e.g. sodium citrate, calcium carbonate and dicalcium phosphate along with various additives such as starch, preferably potato starch, gelatin, etc. in addition to the aforementioned carriers. In addition, lubricants may be used for tabletting purposes. such as magnesium stearate, sodium lauryl sulfate and talc. In the case of aqueous suspensions, various taste-improving substances or dyes can be added to the active compounds in addition to the excipients mentioned.

In accordance with the invention, when administering the compounds of formula I for the treatment of COPD, administration forms or pharmaceutical preparations which can be administered by inhalation are particularly preferably used. Inhalable application forms are inhalable powders, aerosol-containing dosing aerosols or aerosol-free inhalation solutions containing no propellant gas. Within the scope of the invention, the term gas-free inhalation solutions also includes concentrates or ready-to-use sterile inhalation solutions. Application forms used in the context of the invention are described in more detail below.

The inhalable powders used according to the invention may contain the compounds of the formula I alone or in admixture with suitable physiologically compatible auxiliaries. If the active substances of the formula I are present in a mixture with physiologically acceptable auxiliaries, the following physiologically acceptable auxiliaries can be used for the preparation of the inhalation powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose) , oligo- and polysaccharides (e.g. dextran), polyhydric alcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients.

Preferably, mono- or disaccharides are used, especially lactose or glucose, in particular, but not exclusively in the form of hydrates. The excipient used in the context of the invention is in particular lactose, preferably lactose monohydrate.

The inhalation excipients according to the invention have a maximum mean particle size of up to 250 µm, preferably 10-150 µm, in particular 15-80 µm. Alternatively, it may prove advantageous to mix finer excipient fractions with an average particle size of 1-9 μm with the aforementioned excipients. The last-mentioned finely divided auxiliaries are also selected from the group of auxiliaries mentioned above that can be used. Finally, in the preparation of the inhalable powders according to the invention, the micronized active compound of the formula I, preferably with an average particle size of 0.5-10 µm, in particular 1-5 µm, is mixed with the excipient mixture. The method of producing the inhalable powder according to the invention by grinding and micronizing and by further mixing the components is known from the prior art.

The inhalable powders according to the invention can be administered with the aid of inhalers known in the art.

According to the invention, the gas-containing aerosol for inhalation may contain a compound of formula I dissolved or dispersed in the aerosol propellant. The compounds of formula 1 may be present in separate administration forms or in combined administration form, provided that the compounds of formula 1 may either be dissolved, both dispersed, or in each case only one component may be dissolved and the other dispersed. The aerosol propellants used to generate inhalation aerosols are known in the art. Suitable aerosol propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane, and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The aforementioned aerosol propellants can be used alone or as mixtures thereof. Particularly preferred aerosol propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

Inhalation aerosols containing aerosol propellants may further contain further ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All these ingredients are known in the art.

The above-described inhalation aerosols containing aerosolizing gases can be administered by means of inhalers known in the art (MDI = metered dose inhalers = metered dose inhalers).

Furthermore, the active compounds of the formula I according to the invention can be administered in the form of gas-free inhalable aerosol solutions and inhalation suspensions. Suitable solvents are aqueous or alcoholic, preferably ethanolic, solutions. The solvent may be water only or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but preferably the maximum limit is up to 70% by volume, in particular up to 60% by volume, and in particular up to 30% by volume. The remaining percentages by volume are made up with water. Solutions or suspensions containing compounds of the formula I are adjusted to a pH of 2-7, preferably 2-5, with suitable acids. Inorganic or organic acids can be used to adjust this pH value. Examples of particularly preferred inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly preferred organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and the like. The preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which already form an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. It is also possible to use mixtures of the abovementioned acids, in particular for acids which, in addition to acidic properties, also have other properties, e.g. as taste-improving substances, antioxidants or complexing compounds, such as, for example, citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH value.

In these preparations, it is possible to omit the addition of editic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing compound. Other embodiments contain these compounds. In such a preferred embodiment, the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, especially less than 20 mg / 100 ml. In general, inhalation solutions in which the sodium edetate content is 0-10 mg / 100 ml are preferred. Cosolvents and / or further auxiliaries may be added to the aerosolytic aerosol-free inhalation solutions. Co-solvents containing hydroxyl groups or other polar groups are preferred, for example alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerin, polyoxyethylene alcohols and fatty acid esters.

PL 212 238 B1 and polyoxyethylene. In this case, auxiliaries and additives are understood to mean any pharmacologically acceptable substance which is not an active ingredient, but can be formulated together with the active ingredients with a suitable solvent in order to improve the qualitative properties of the active ingredient formulation. Preferably, these substances do not develop any remarkable or at least no undesirable pharmacological effect either in connection with the intended therapy. Auxiliaries and additives include, for example, surface-active substances such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing substances, antioxidants and / or preservatives which provide or prolong the life of the using finished drug formulations, taste-improving substances, vitamins and / or other additives known in the art.

The additives also include pharmacologically acceptable salts such as, for example, sodium chloride, as isotonic agents.

The preferred excipients include antioxidants such as, for example, ascorbic acid, if not already used to adjust the pH value, vitamin A, vitamin E, tocopherol and similar vitamins or provitamins occurring in the human body.

Preservatives can be used to protect the formulation from microbial contamination. Suitable preservatives are substances known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in concentrations known from the prior art. The above-mentioned preservatives are preferably present in a concentration of up to 50 mg / 100 ml, in particular 5-20 mg / 100 ml. Preferred formulations contain only benzalkonium chloride and sodium edetate in addition to water as solvent and active ingredient of the formula I.

In another preferred embodiment, sodium edetate is dispensed with.

The dosage of the compounds of the invention depends largely on the mode of administration and the condition being treated. When administered by inhalation, the compounds of formula I are already highly active in doses in the μg range. The compounds of formula 1 can also be used advantageously above the pg range. The dosage can then also be in the gram range, for example.

A further aspect of the invention relates to the abovementioned pharmaceutical preparations, which are characterized in that they contain a compound of formula I as such, particularly preferably the abovementioned pharmaceutical preparations that can be administered by inhalation.

The following formulation examples illustrate the invention without limiting its scope.

Examples of pharmaceutical preparations

A) Tablets per tablet The active substance of the formula 1 100 mg Milk sugar 140 mg Corn starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg

500 mg

The finely ground active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is passed through a sieve, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are passed through a sieve and mixed together. The mixture is pressed into tablets of the appropriate form and size.

B) Tablets per tablet The active substance of the formula 1 80 mg Milk sugar 55 mg Corn starch 190 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Sodium derivative of carboxymethyl starch 23 mg Magnesium stearate 2 mg

400 mg

The finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is passed through a sieve and with the remainder

The amount of corn starch and water are processed into granules, which are dried and passed through a sieve. Thereto, sodium carboxymethyl starch and magnesium stearate are added, mixed and the mixture pressed into tablets of the appropriate size.

C) Ampoule solution

Active ingredient of formula 1 50 mg

Sodium chloride 50 mg

Water for injection 5 ml

The active ingredient is dissolved in water at its own pH value or, if appropriate, at pH 5.5-6.5, and sodium chloride is added as isotonic agent. The solution obtained is filtered to a pyrogen-free state and the filtrate is aseptically filled into ampoules, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg of the active ingredient.

D) Dosing aerosol

Active ingredient of formula 1 0.005

Sorbitan trioleate 0.1

Monofluorotrichloromethane and TG134a: TG227 2: 1 to 100

The suspension is filled into a conventional aerosol canister with a dosing valve. Preferably 50 μ of suspension is obtained in one shot. The active ingredient can also, if desired, be administered in higher doses (e.g. 0.02% by weight).

E) Solutions (in mg / 100 ml)

Active substance of the formula 1 333.3 mg

Benzalkonium chloride 10.0 mg EDTA 500.0 mg

HCl (1N) to pH 3.4

This solution can be prepared in a known manner.

F) Inhalation powder

Active substance of the formula 1 12 μg

Lactose monohydrate up to 25 mg

The inhalation powder is prepared in a known manner by mixing the individual components.

Claims (25)

1. Compounds of general formula 1: wherein: n is 1, ₁ R ¹ represents a hydrogen atom, a halogen atom, a C1-C4-alkyl or a -O-C1-C4-alkyl group, ₂ R ² is hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₃ R ³ is C1-C4-alkyl, OH, halogen, -O-C1-C4-alkyl, -O-C1-C4-alkyl-leneCOOH or -O-C1-C4-alkylene-CO-O- C1-C4-alkyl, provided that when R ¹ and R ² are each ortho methyl, R ³ cannot simultaneously represent an OH group. 2. Compounds of general formula 1 according to claim 1 1, in which: n is 1, ₁ R ¹ is hydrogen, fluoro, chloro, methyl or methoxy, ₂ R ² is hydrogen, fluoro, chloro, methyl or methoxy, ₃ R ³ is C1-C4-alkyl, OH, fluorine, chlorine, bromine, -O-C1-C4-alkyl, -O-C1-C4-alkylene-COOH, -O-C1-C4-alkylene-CO -O-C1-C4-alkyl, with the proviso that when R ¹ and R ² ₃ are each a methyl group at the ortho position, R ³ may not simultaneously represent OH group. PL 212 238 B1 3. Compounds of general formula 1 according to claim 1 1, in which: n is 1, ₁ R ¹ is hydrogen or C 1 -C 4 -alkyl, ₂ ^R2 is hydrogen or C1-C4-alkyl, R ³ is C1-C4-alkyl, OH, -O-C1-C4-alkyl, -O-C1-C4-alkylene-COOH or -O-C1-C4-alkylene-CO-O-C1-C4-alkyl , 1 2 3 with the proviso that when R ¹ and R ² are each ortho methyl, R ³ cannot simultaneously be an OH group. 4. Compounds of general formula 1 according to claim 1 1, in which: n is 1, ₁ R ¹ is hydrogen, methyl or ethyl, ₂ R ² is hydrogen, methyl or ethyl, ₃ R ³ is methyl, ethyl, OH, methoxy, ethoxy, -O-CH2-COOH group, -O12 group -CH2-COO-methyl or -O-CH2-CO-ethyl, with the proviso that when R ¹ and R ² each represent a methyl group, a ₃ in the ortho-position, R ³ may not simultaneously represent OH group. ₃ Compounds of general formula 1 according to any one of claims 1 to 5 1-4 where: R ³ is methoxy, ethoxy, -O-CH2-COOH, -O-CH2-COO-methyl or -O-CH2-COO-ethyl, 12 and R ¹ , R ^{2 and} n have previously given meaning. 6. Compounds of general formula 1 according to claim 1 1, in which: n is 1, ₁ R ¹ is halogen, C1-C4-alkyl, or -O-C1-C4-alkyl, ₂ R ² is halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₃ R ³ is halogen, C1-C4-alkyl or -O-C1-C4-alkyl. Compounds of general formula 1 according to claim 1 6, in which: n is 1, ₁ R ¹ is fluoro, chloro, methyl or methoxy, ₂ R ² is fluoro, chloro, methyl or methoxy, ₃ R ³ is fluoro, chloro, methyl or methoxy. 8. Compounds of general formula 1 according to claim 1 1, in which: n is 1, ₁ R ¹ is hydrogen, ₂ R ² is hydrogen, fluoro, chloro or methyl, ₃ R ³ is methyl, ethyl, isopropyl, t-butyl, CH, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH2-COOH, -O-CH2-CH2-COOH, -O-CH2-CH2 -CH2- COOH, -O-CH2-COO-methyl, -O-CH2-COO-ethyl, -O-CH2-CH2-COO-methyl, -O-CH2-CH2COO-ethyl, -O-CH2-CH2 -CH2-COO-methyl, -O-CH2-CH2-CH2-COO-ethyl. 9. Compounds of general formula 1 according to claim 1 8, in which: n is 1, ₁ R ¹ is hydrogen, ₂ R ² is hydrogen, fluoro, chloro or methyl, ₃ R ³ is OH, fluoro, chloro, methyl, methoxy, ethoxy or -O-CH2-COOH. 10. Compounds of general formula 1 according to claim 1 8, in which: n is 1, R ¹ and R ² are hydrogen, ₃ R ³ is methyl, ethyl, isopropyl, t-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, -O-CH2-COOH, -O-CH2-CH2-COOH, -O-CH2-CH2 -CH2- COOH, -O-CH2-COO-methyl, -O-CH2-COO-ethyl, -O-CH2-CH2-COO-methyl, -O-CH2-CH2COO-ethyl, -O-CH2-CH2 -CH2-COO-methyl, -O-CH2-CH2-CH2-COO-ethyl. 11. Compounds of general formula 1 according to claim 1 10, in which: n is 1, R ¹ and R ² are hydrogen, ₃ R ³ is OH, fluoro, chloro, methoxy, ethoxy, -O-CH2-COOH, preferably OH, fluoro, chloro, ethoxy or methoxy. PL 212 238 B1 12. Compounds of general formula 1 according to claim 1 1, in which: n is 1, ₁ R ¹ is hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₂ R ² is hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl, ₃ R ³ is hydrogen. 13. Compounds of general formula 1 according to claim 1 12, in which: n is 1, ₁ R ¹ is hydrogen, fluoro, chloro, methyl or methoxy, ₂ R ² is hydrogen, fluoro, chloro, methyl or methoxy, ₃ R ³ is hydrogen. 14. A compound of general formula 1 according to claim 1 The compound of claim 1, wherein the compound has the following structure: 15. A compound of general formula 1 according to claim 1 The compound of claim 1, wherein the compound has the following structure: 16. A compound of general formula 1 according to claim 1 The compound of claim 1, wherein the compound has the following structure: 17. A compound of general formula 1 according to claim 1 in which the compound has the following structure: 18. A compound of general formula 1 according to claim 1 in which the compound has the following structure: PL 212 238 B1 19. Compounds of general formula 1 according to any one of claims 1 to 19 1-18, in which the compounds of formula I exist as individual optical isomers, mixtures of individual enantiomers or racemates, preferably in the form of enantiomerically pure compounds. 20. Compounds of the general formula 1 according to any one of the preceding claims 1-18, in which the compounds of formula I are in the form of addition salts with pharmacologically acceptable acids and, optionally, in the form of solvates and / or hydrates. 21. Use of compounds of general formula 1 as defined in any one of claims 1 to 21 1-20, as medicaments. 22. The use of compounds of general formula 1 as defined in any one of claims 1 to 22 1-20, for the manufacture of a medicament for treating chronic obstructive pulmonary disease COPD. 23. A pharmaceutical preparation containing a compound of general formula 1 as defined in one of the claims 1 to 23. 1-20. 24. Pharmaceutical preparation for administration by inhalation, comprising a compound of the general formula I as defined in any one of claims 1 to 24. 1 to 20. 25. A pharmaceutical formulation for administration by inhalation according to claim 1, The method of claim 24, which is selected from the group consisting of inhalable powders, aerosols for dosing containing an aerosolizing gas, and inhalation solutions free of aerosolizing gases.